The expression of specific genes is dependent on the interaction of nuclear proteins with the promoter regions of the genes. We have identified nuclear proteins that act as activators or repressors of EGFR gene expression. EGF receptor gene expression is stimulated by phorbol esters. We have determined that phorbol ester induction of the EGFR gene is mediated via activator protein 2 (AP2). Transient transfection assays and nuclear runoff experiments with promoter mutants showed that phorbol esters increased EGF receptor gene transcription and that the region of the promoter containing nucleotides -150 to -16 was sufficient for phorbol ester inducibility. A partially purified phorbol ester induced factor and purified AP2 were shown to have virtually identical DNase I footprints on the EGF receptor promoter. AP2 was shown to bind to five sites in the EGFR promoter. Addition of AP2 to nuclear extract resulted in increased transcription from the EGF receptor promoter. These results demonstrated that AP2 can activate EGF receptor gene expression and mediates the phorbol ester response of this gene. We have recently identified a transcription factor termed GCF2. GCF2 has been shown to bind to the EGFR promoter and repress transcription of the gene. Antiserum produced against bacterially expressed GCF2 was used to show that GCF2 in cells migrates as a 160 kilodalton protein and is located in nuclear and cytoplasmic compartments. The 160 kilodalton size is consistent with in vitro produced protein but substantially different from the calculated size based on cDNA sequence. GCF2 is expressed at high levels in Raji cells and HUT102 cells, lymphoma cell lines, and lower levels in other cancer cell lines.